US20110034457A1 - Pyridothiophene Compounds - Google Patents
Pyridothiophene Compounds Download PDFInfo
- Publication number
- US20110034457A1 US20110034457A1 US12/909,014 US90901410A US2011034457A1 US 20110034457 A1 US20110034457 A1 US 20110034457A1 US 90901410 A US90901410 A US 90901410A US 2011034457 A1 US2011034457 A1 US 2011034457A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- nhr
- conr
- coor
- conhr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical class C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 title description 3
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 claims abstract description 50
- 101710113864 Heat shock protein 90 Proteins 0.000 claims abstract description 48
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 38
- 230000000694 effects Effects 0.000 claims abstract description 26
- 125000001424 substituent group Chemical group 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000000565 sulfonamide group Chemical group 0.000 claims abstract description 5
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- -1 4-pyridinyl Chemical group 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000002837 carbocyclic group Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 11
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 150000002825 nitriles Chemical class 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000004043 oxo group Chemical group O=* 0.000 claims description 11
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000003107 substituted aryl group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000004450 alkenylene group Chemical group 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 2
- 230000001404 mediated effect Effects 0.000 abstract description 4
- 150000001733 carboxylic acid esters Chemical group 0.000 abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 150000003857 carboxamides Chemical group 0.000 abstract description 2
- 239000012453 solvate Substances 0.000 abstract description 2
- 108090000623 proteins and genes Proteins 0.000 description 28
- 102000004169 proteins and genes Human genes 0.000 description 26
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 13
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 13
- 108010006519 Molecular Chaperones Proteins 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 9
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 description 9
- 102000005431 Molecular Chaperones Human genes 0.000 description 8
- 238000003556 assay Methods 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 0 [2*]C1=C2C(=NC(N)=C1C#N)SC([4*])=C2[3*] Chemical compound [2*]C1=C2C(=NC(N)=C1C#N)SC([4*])=C2[3*] 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- QTQAWLPCGQOSGP-KSRBKZBZSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-KSRBKZBZSA-N 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- VYGYNVZNSSTDLJ-HKCOAVLJSA-N monorden Natural products CC1CC2OC2C=C/C=C/C(=O)CC3C(C(=CC(=C3Cl)O)O)C(=O)O1 VYGYNVZNSSTDLJ-HKCOAVLJSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- AECPBJMOGBFQDN-YMYQVXQQSA-N radicicol Chemical compound C1CCCC(=O)C[C@H]2[C@H](Cl)C(=O)CC(=O)[C@H]2C(=O)O[C@H](C)C[C@H]2O[C@@H]21 AECPBJMOGBFQDN-YMYQVXQQSA-N 0.000 description 5
- 229930192524 radicicol Natural products 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 108091006112 ATPases Proteins 0.000 description 4
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000002875 fluorescence polarization Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 238000003828 vacuum filtration Methods 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- 102100039328 Endoplasmin Human genes 0.000 description 3
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910003827 NRaRb Inorganic materials 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 108010017007 glucose-regulated proteins Proteins 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000004807 localization Effects 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- KTPFGSXXUDJFFQ-UHFFFAOYSA-N 2-amino-4-phenyl-6-sulfanylidene-1h-pyridine-3,5-dicarbonitrile Chemical compound N#CC1=C(N)NC(=S)C(C#N)=C1C1=CC=CC=C1 KTPFGSXXUDJFFQ-UHFFFAOYSA-N 0.000 description 2
- WAVNYPVYNSIHNC-UHFFFAOYSA-N 2-benzylidenepropanedinitrile Chemical compound N#CC(C#N)=CC1=CC=CC=C1 WAVNYPVYNSIHNC-UHFFFAOYSA-N 0.000 description 2
- WBLWZOPFZBZTMS-UHFFFAOYSA-N 3,6-diamino-5-cyano-4-phenylthieno[2,3-b]pyridine-2-carboxylic acid Chemical compound C=12C(N)=C(C(O)=O)SC2=NC(N)=C(C#N)C=1C1=CC=CC=C1 WBLWZOPFZBZTMS-UHFFFAOYSA-N 0.000 description 2
- LDEPBCWUHROCIN-UHFFFAOYSA-N 3,6-diamino-5-cyano-n-ethyl-4-phenylthieno[2,3-b]pyridine-2-carboxamide Chemical compound C=12C(N)=C(C(=O)NCC)SC2=NC(N)=C(C#N)C=1C1=CC=CC=C1 LDEPBCWUHROCIN-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- RJOPKBVOZPWSCU-UHFFFAOYSA-N CC1=CC=CC=C1NC(=O)C1=C(N)C2=C(N=C(N)C(C#N)=C2C2=CC=C(C(C)C)C=C2)S1 Chemical compound CC1=CC=CC=C1NC(=O)C1=C(N)C2=C(N=C(N)C(C#N)=C2C2=CC=C(C(C)C)C=C2)S1 RJOPKBVOZPWSCU-UHFFFAOYSA-N 0.000 description 2
- UOPQHPBCVYHSFF-UHFFFAOYSA-N CCOC1=CC=C(C2=C(C#N)C(N)=NC3=C2C(N)=C(C(N)=O)S3)C=C1 Chemical compound CCOC1=CC=C(C2=C(C#N)C(N)=NC3=C2C(N)=C(C(N)=O)S3)C=C1 UOPQHPBCVYHSFF-UHFFFAOYSA-N 0.000 description 2
- GTWKOSHRMWFVKR-UHFFFAOYSA-N CN1CCN(C(=O)C2=C(N)C3=C(C4=CC=CC=C4)C(C#N)=C(N)N=C3S2)CC1 Chemical compound CN1CCN(C(=O)C2=C(N)C3=C(C4=CC=CC=C4)C(C#N)=C(N)N=C3S2)CC1 GTWKOSHRMWFVKR-UHFFFAOYSA-N 0.000 description 2
- 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 102100026973 Heat shock protein 75 kDa, mitochondrial Human genes 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- LBIXJEUYRCVEJE-UHFFFAOYSA-N N#CC1=C(N)N=C2SC(C(=O)N3CCOCC3)=C(N)C2=C1C1=CC=CC=C1 Chemical compound N#CC1=C(N)N=C2SC(C(=O)N3CCOCC3)=C(N)C2=C1C1=CC=CC=C1 LBIXJEUYRCVEJE-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- YJQPYGGHQPGBLI-UHFFFAOYSA-N Novobiocin Natural products O1C(C)(C)C(OC)C(OC(N)=O)C(O)C1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 101710204707 Transforming growth factor-beta receptor-associated protein 1 Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000012866 crystallographic experiment Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000002074 deregulated effect Effects 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- 230000006353 environmental stress Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- BHTNSGLNVCGPLC-UHFFFAOYSA-N ethyl 3,6-diamino-5-cyano-4-phenylthieno[2,3-b]pyridine-2-carboxylate Chemical compound C=12C(N)=C(C(=O)OCC)SC2=NC(N)=C(C#N)C=1C1=CC=CC=C1 BHTNSGLNVCGPLC-UHFFFAOYSA-N 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- YJQPYGGHQPGBLI-KGSXXDOSSA-N novobiocin Chemical compound O1C(C)(C)[C@H](OC)[C@@H](OC(N)=O)[C@@H](O)[C@@H]1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-KGSXXDOSSA-N 0.000 description 2
- 229960002950 novobiocin Drugs 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000022983 regulation of cell cycle Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 230000008684 selective degradation Effects 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- MKYRMMMSZSVIGD-UHFFFAOYSA-N thieno[3,2-c]pyridine Chemical compound N1=CC=C2SC=CC2=C1 MKYRMMMSZSVIGD-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 2
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- BHPYMZQTCPRLNR-UHFFFAOYSA-N 2-cyanoethanethioamide Chemical compound NC(=S)CC#N BHPYMZQTCPRLNR-UHFFFAOYSA-N 0.000 description 1
- JXPDNDHCMMOJPC-UHFFFAOYSA-N 2-hydroxybutanedinitrile Chemical compound N#CC(O)CC#N JXPDNDHCMMOJPC-UHFFFAOYSA-N 0.000 description 1
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 102100035634 B-cell linker protein Human genes 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- FHGNMBQQUFOOLH-UHFFFAOYSA-N CC(C)C1=CC=C(C2=C(C#N)C(N)=NC3=C2C(N)=C(C(=O)NC2=NC=CS2)S3)C=C1 Chemical compound CC(C)C1=CC=C(C2=C(C#N)C(N)=NC3=C2C(N)=C(C(=O)NC2=NC=CS2)S3)C=C1 FHGNMBQQUFOOLH-UHFFFAOYSA-N 0.000 description 1
- APOVRUDMMNQNFL-UHFFFAOYSA-N CC(C)C1=CC=C(C2=C(C#N)C(N)=NC3=C2C(N)=C(C(N)=O)S3)C=C1 Chemical compound CC(C)C1=CC=C(C2=C(C#N)C(N)=NC3=C2C(N)=C(C(N)=O)S3)C=C1 APOVRUDMMNQNFL-UHFFFAOYSA-N 0.000 description 1
- JLOXHJFYHMIXGS-UHFFFAOYSA-N CC(C)CC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 Chemical compound CC(C)CC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 JLOXHJFYHMIXGS-UHFFFAOYSA-N 0.000 description 1
- PCYOSAGCEIDTPG-UHFFFAOYSA-N CCC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 Chemical compound CCC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 PCYOSAGCEIDTPG-UHFFFAOYSA-N 0.000 description 1
- PYIGRRSCSKVCEB-UHFFFAOYSA-N CCCC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 Chemical compound CCCC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 PYIGRRSCSKVCEB-UHFFFAOYSA-N 0.000 description 1
- RDXXVMULXRMDPH-UHFFFAOYSA-N CCN(CC)C(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 Chemical compound CCN(CC)C(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 RDXXVMULXRMDPH-UHFFFAOYSA-N 0.000 description 1
- KLNROJXCDDCWPS-UHFFFAOYSA-N CN(C)CCCC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 Chemical compound CN(C)CCCC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 KLNROJXCDDCWPS-UHFFFAOYSA-N 0.000 description 1
- QQQCXRWPWIBXPY-UHFFFAOYSA-N CN(C)CCCCC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 Chemical compound CN(C)CCCCC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 QQQCXRWPWIBXPY-UHFFFAOYSA-N 0.000 description 1
- YBRBGRCZBIVQOD-UHFFFAOYSA-N CN1CCN(CCCCC(=O)C2=C(N)C3=C(C4=CC=CC=C4)C(C#N)=C(N)N=C3S2)CC1 Chemical compound CN1CCN(CCCCC(=O)C2=C(N)C3=C(C4=CC=CC=C4)C(C#N)=C(N)N=C3S2)CC1 YBRBGRCZBIVQOD-UHFFFAOYSA-N 0.000 description 1
- PQVDGDCPBIEVQW-UHFFFAOYSA-N COC(=O)C1=C(N)C2=C(C3=CC=C(OC(C)C)C=C3)C(C#N)=C(N)N=C2S1 Chemical compound COC(=O)C1=C(N)C2=C(C3=CC=C(OC(C)C)C=C3)C(C#N)=C(N)N=C2S1 PQVDGDCPBIEVQW-UHFFFAOYSA-N 0.000 description 1
- PFGKWBNUBDMCOS-UHFFFAOYSA-N COC(=O)CCC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 Chemical compound COC(=O)CCC(=O)C1=C(N)C2=C(C3=CC=CC=C3)C(C#N)=C(N)N=C2S1 PFGKWBNUBDMCOS-UHFFFAOYSA-N 0.000 description 1
- ZWLMGVUDHASCAP-UHFFFAOYSA-N COC1=C(OC)C=C(C2=C3C(=NC(N)=C2C#N)SC(C(N)=O)=C3N)C=C1 Chemical compound COC1=C(OC)C=C(C2=C3C(=NC(N)=C2C#N)SC(C(N)=O)=C3N)C=C1 ZWLMGVUDHASCAP-UHFFFAOYSA-N 0.000 description 1
- VAPMULXLBFFEEQ-UHFFFAOYSA-N COC1=CC(NC(=O)C2=C(N)C3=C(N=C(N)C(C#N)=C3C3=CC=C(C(C)C)C=C3)S2)=CC=C1 Chemical compound COC1=CC(NC(=O)C2=C(N)C3=C(N=C(N)C(C#N)=C3C3=CC=C(C(C)C)C=C3)S2)=CC=C1 VAPMULXLBFFEEQ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 1
- 101710163595 Chaperone protein DnaK Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 102000005623 HSP27 Heat-Shock Proteins Human genes 0.000 description 1
- 108010045100 HSP27 Heat-Shock Proteins Proteins 0.000 description 1
- 101710178376 Heat shock 70 kDa protein Proteins 0.000 description 1
- 101710152018 Heat shock cognate 70 kDa protein Proteins 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- MCAHMSDENAOJFZ-UHFFFAOYSA-N Herbimycin A Natural products N1C(=O)C(C)=CC=CC(OC)C(OC(N)=O)C(C)=CC(C)C(OC)C(OC)CC(C)C(OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-UHFFFAOYSA-N 0.000 description 1
- 101000803266 Homo sapiens B-cell linker protein Proteins 0.000 description 1
- 101001047681 Homo sapiens Tyrosine-protein kinase Lck Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 108700005084 Multigene Family Proteins 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- BQSJCYZRXJIBLE-UHFFFAOYSA-N N#CC1=C(C2=CC=C(Br)C=C2)C2=C(N=C1N)SC(C(=O)CC1=CC=CC=C1)=C2N Chemical compound N#CC1=C(C2=CC=C(Br)C=C2)C2=C(N=C1N)SC(C(=O)CC1=CC=CC=C1)=C2N BQSJCYZRXJIBLE-UHFFFAOYSA-N 0.000 description 1
- DHJPTCOCQOYLAD-UHFFFAOYSA-N N#CC1=C(C2=CC=C(Cl)C=C2)C2=C(N=C1N)SC(C(N)=O)=C2N Chemical compound N#CC1=C(C2=CC=C(Cl)C=C2)C2=C(N=C1N)SC(C(N)=O)=C2N DHJPTCOCQOYLAD-UHFFFAOYSA-N 0.000 description 1
- NHWNRNUNHRKOAU-UHFFFAOYSA-N N#CC1=C(N)N=C2SC(C(=O)CCC(N)=O)=C(N)C2=C1C1=CC=CC=C1 Chemical compound N#CC1=C(N)N=C2SC(C(=O)CCC(N)=O)=C(N)C2=C1C1=CC=CC=C1 NHWNRNUNHRKOAU-UHFFFAOYSA-N 0.000 description 1
- OBKCTMHIKSJJBT-UHFFFAOYSA-N N#CC1=C(N)N=C2SC(C(=O)CCC3=CC=CC=C3)=C(N)C2=C1C1=CC=CC=C1 Chemical compound N#CC1=C(N)N=C2SC(C(=O)CCC3=CC=CC=C3)=C(N)C2=C1C1=CC=CC=C1 OBKCTMHIKSJJBT-UHFFFAOYSA-N 0.000 description 1
- LBSZRLUAQAJMTR-UHFFFAOYSA-N N#CC1=C(N)N=C2SC(C(=O)CCCCN3CCOCC3)=C(N)C2=C1C1=CC=CC=C1 Chemical compound N#CC1=C(N)N=C2SC(C(=O)CCCCN3CCOCC3)=C(N)C2=C1C1=CC=CC=C1 LBSZRLUAQAJMTR-UHFFFAOYSA-N 0.000 description 1
- KHJLATHYLMFNAE-UHFFFAOYSA-N N#CC1=C(N)N=C2SC(C(=O)CCCN)=C(N)C2=C1C1=CC=CC=C1 Chemical compound N#CC1=C(N)N=C2SC(C(=O)CCCN)=C(N)C2=C1C1=CC=CC=C1 KHJLATHYLMFNAE-UHFFFAOYSA-N 0.000 description 1
- LGIVYMVAPHEJQQ-UHFFFAOYSA-N N#CC1=C(N)N=C2SC(C(=O)CCCN3CCOCC3)=C(N)C2=C1C1=CC=CC=C1 Chemical compound N#CC1=C(N)N=C2SC(C(=O)CCCN3CCOCC3)=C(N)C2=C1C1=CC=CC=C1 LGIVYMVAPHEJQQ-UHFFFAOYSA-N 0.000 description 1
- DIQYZKXQABSANV-UHFFFAOYSA-N N#CC1=C(N)N=C2SC(C(=O)CCCO)=C(N)C2=C1C1=CC=CC=C1 Chemical compound N#CC1=C(N)N=C2SC(C(=O)CCCO)=C(N)C2=C1C1=CC=CC=C1 DIQYZKXQABSANV-UHFFFAOYSA-N 0.000 description 1
- CLAHOAYDTIRDIV-UHFFFAOYSA-N N#CC1=C(N)N=C2SC(C(N)=O)=C(N)C2=C1C1=CC=C(Br)C=C1 Chemical compound N#CC1=C(N)N=C2SC(C(N)=O)=C(N)C2=C1C1=CC=C(Br)C=C1 CLAHOAYDTIRDIV-UHFFFAOYSA-N 0.000 description 1
- TYEHUZZBGBJVKD-UHFFFAOYSA-N N#CC1=C(N)N=C2SC(C(N)=O)=C(N)C2=C1C1=CC=CC=C1 Chemical compound N#CC1=C(N)N=C2SC(C(N)=O)=C(N)C2=C1C1=CC=CC=C1 TYEHUZZBGBJVKD-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 241001417528 Nematistiidae Species 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- YZINASHKXHZHNQ-UHFFFAOYSA-N O=C1C=CC2=C(C3=C(C(=O)O)C=C(C(=O)NCC4=CC=C(C5=CNN=C5C5=CC(Cl)=C(O)C=C5O)C=C4)C=C3)C3=C(C=C(O)C=C3)OC2=C1 Chemical compound O=C1C=CC2=C(C3=C(C(=O)O)C=C(C(=O)NCC4=CC=C(C5=CNN=C5C5=CC(Cl)=C(O)C=C5O)C=C4)C=C3)C3=C(C=C(O)C=C3)OC2=C1 YZINASHKXHZHNQ-UHFFFAOYSA-N 0.000 description 1
- 108010058765 Oncogene Protein pp60(v-src) Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical class [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 1
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000018594 Tumour necrosis factor Human genes 0.000 description 1
- 108050007852 Tumour necrosis factor Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 102100024036 Tyrosine-protein kinase Lck Human genes 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000007080 aromatic substitution reaction Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000035567 cellular accumulation Effects 0.000 description 1
- 230000007960 cellular response to stress Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001876 chaperonelike Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000000198 fluorescence anisotropy Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- MCAHMSDENAOJFZ-BVXDHVRPSA-N herbimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](OC)[C@@H](OC)C[C@H](C)[C@@H](OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-BVXDHVRPSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical class [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 235000012254 magnesium hydroxide Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000004879 molecular function Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000004650 oncogenic pathway Effects 0.000 description 1
- 230000006548 oncogenic transformation Effects 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 208000008864 scrapie Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 108700026239 src Genes Proteins 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Definitions
- This invention relates to substituted bicyclic thieno[2,3-d]pyridine (herein referred to as ‘pyridothiophene’) compounds having HSP90 inhibitory activity, to the use of such compounds in medicine, in relation to diseases which are mediated by excessive or inappropriate HSP90 activity such as cancers, and to pharmaceutical compositions containing such compounds.
- pyridothiophene substituted bicyclic thieno[2,3-d]pyridine
- HSPs Heat Shock Proteins
- HSPs heat shock proteins
- HSPs multigene families of HSPs exist, with individual gene products varying in cellular expression, function and localization. They are classified according to molecular weight, e.g., HSP70, HSP90, and HSP27.
- Several diseases in humans can be acquired as a result of protein misfolding (reviewed in Tytell et al., 2001; Smith et al., 1998).
- therapies which disrupt the molecular chaperone machinery may prove to be beneficial.
- misfolded proteins can cause protein aggregation resulting in neurodegenerative disorders.
- misfolded proteins may result in loss of wild type protein function, leading to deregulated molecular and physiological functions in the cell.
- HSPs have also been implicated in cancer. For example, there is evidence of differential expression of HSPs which may relate to the stage of tumour progression (Martin et al., 2000; Conroy et al., 1996; Kawanishi et al., 1999; Jameel et al., 1992; Hoang et al., 2000; Lebeau et al., 1991).
- HSP90 in various critical oncogenic pathways and the discovery that certain natural products with anticancer activity are targeting this molecular chaperone
- the first molecular chaperone inhibitor is currently undergoing clinical trials.
- HSP90 constitutes about 1-2% of total cellular protein, and is usually present in the cell as a dimer in association with one of a number of other proteins (see, e.g., Pratt, 1997). It is essential for cell viability and it exhibits dual chaperone functions (Young et al., 2001). It plays a key role in the cellular stress response by interacting with many proteins after their native conformation has been altered by various environmental stresses, such as heat shock, ensuring adequate protein folding and preventing non-specific aggregation (Smith et al., 1998). In addition, recent results suggest that HSP90 may also play a role in buffering against the effects of mutation, presumably by correcting the inappropriate folding of mutant proteins (Rutherford and Lindquist, 1998).
- HSP90 also has an important regulatory role. Under normal physiological conditions, together with its endoplasmic reticulum homologue GRP94, HSP90 plays a housekeeping role in the cell, maintaining the conformational stability and maturation of several key client proteins. These can be subdivided into three groups: (a) steroid hormone receptors, (b) Ser/Thr or tyrosine kinases (e.g., ERBB2, RAF-1, CDK4, and LCK), and (c) a collection of apparently unrelated proteins, e.g., mutant p53 and the catalytic subunit of telomerase hTERT. All of these proteins play key regulatory roles in many physiological and biochemical processes in the cell. New HSP90 client proteins are continuously being identified.
- HSP90 The highly conserved HSP90 family in humans consists of four genes, namely the cytosolic HSP90a and HSP908 isoforms (Hickey et al., 1989), GRP94 in the endoplasmic reticulum (Argon et al., 1999) and FISP75/TRAP1 in the mitochondrial matrix (Felts et al., 2000). It is thought that all the family members have a similar mode of action, but bind to different client proteins depending on their localization within the cell.
- ERBB2 is known to be a specific client protein of GRP94 (Argon et al., 1999) and type 1 tumour necrosis factor receptor (INFR1) and RB have both been shown to be clients of TRAP1 (Song et al., 1995; Chen et al., 1996).
- HSP90 participates in a series of complex interactions with a range of client and regulatory proteins (Smith, 2001). Although the precise molecular details remain to be elucidated, biochemical and X-ray crystallographic studies (Prodromou et al., 1997; Stebbins et al., 1997) carried out over the last few years have provided increasingly detailed insights into the chaperone function of HSP90.
- HSP90 is an ATP-dependent molecular chaperone (Prodromou et al, 1997), with dimerization of the nucleotide binding domains being essential for ATP hydrolysis, which is in turn essential for chaperone function (Prodromou et al, 2000a). Binding of ATP results in the formation of a toroidal dimer structure in which the N terminal domains are brought into closer contact with each other resulting in a conformational switch known as the ‘clamp mechanism’ (Prodromou and Pearl, 2000b).
- the first class of HSP90 inhibitors to be discovered was the benzoquinone ansamycin class, which includes the compounds herbimycin A and geldanamycin. They were shown to reverse the malignant phenotype of fibroblasts transformed by the v-Src oncogene (Uehara et al., 1985), and subsequently to exhibit potent antitumour activity in both in vitro (Schulte et al., 1998) and in vivo animal models (Supko et al., 1995).
- 17-Allylamino, 17-demethoxygeldanamycin retains the property of HSP90 inhibition resulting in client protein depletion and antitumour activity in cell culture and xenograft models (Schulte et al, 1998; Kelland et al, 1999), but has significantly less hepatotoxicity than geldanamycin (Page et al, 1997). 17AAG is currently being evaluated in Phase I clinical trials.
- Radicicol is a macrocyclic antibiotic shown to reverse the malignant phenotype of v-Src and v-Ha-Ras transformed fibroblasts (Kwon et al, 1992; Zhao et al, 1995). It was shown to degrade a number of signalling proteins as a consequence of HSP90 inhibition (Schulte et al., 1998). X-ray crystallographic data confirmed that radicicol also binds to the N terminal domain of HSP90 and inhibits the intrinsic ATPase activity (Roe et al., 1998). Radicicol lacks antitumour activity in vivo due to the unstable chemical nature of the compound.
- a purine-based HSP90 inhibitor, PU3 has been shown to result in the degradation of signalling molecules, including ERBB2, and to cause cell cycle arrest and differentiation in breast cancer cells (Chiosis et al., 2001).
- HSP90 Due to its involvement in regulating a number of signalling pathways that are crucially important in driving the phenotype of a tumour, and the discovery that certain bioactive natural products exert their effects via HSP90 activity, the molecular chaperone HSP90 is currently being assessed as a new target for anticancer drug development (Neckers et al., 1999).
- geldanamycin, 17AAG, and radicicol The predominant mechanism of action of geldanamycin, 17AAG, and radicicol involves binding to HSP90 at the ATP binding site located in the N-terminal domain of the protein, leading to inhibition of the intrinsic ATPase activity of HSP90 (see, e.g., Prodromou et al., 1997; Stebbins et al., 1997; Panaretou et al., 1998).
- HSP90 ATPase activity prevents recruitment of co-chaperones and encourages the formation of a type of HSP90 heterocomplex from which these client proteins are targeted for degradation via the ubiquitin proteasome pathway (see, e.g., Neckers et al., 1999; Kelland et al., 1999).
- HSP90 inhibitors Treatment with HSP90 inhibitors leads to selective degradation of important proteins involved in cell proliferation, cell cycle regulation and apoptosis, processes which are fundamentally important in cancer.
- HSP90 function has been shown to cause selective degradation of important signalling proteins involved in cell proliferation, cell cycle regulation and apoptosis, processes which are fundamentally important and which are commonly deregulated in cancer (see, e.g., Hostein et al., 2001).
- An attractive rationale for developing drugs against this target for use in the clinic is that by simultaneously depleting proteins associated with the transformed phenotype, one may obtain a strong antitumour effect and achieve a therapeutic advantage against cancer versus normal cells.
- These events downstream of HSP90 inhibition are believed to be responsible for the antitumour activity of HSP90 inhibitors in cell culture and animal models (see, e.g., Schulte et al., 1998; Kelland et al., 1999).
- the present invention relates to the use of a class of substituted thieno[2,3-d]pyridine compounds (referred to herein as pyridothiophenes) as HSP90 inhibitors, for example for inhibition of cancer cell proliferation.
- pyridothiophenes a class of substituted thieno[2,3-d]pyridine compounds
- a core pyridothiophene ring system with amino, cyano and aromatic substitution on the pyrido ring are principle characterising features of the compounds with which the invention is concerned.
- the present invention provides the use of a compound of formula (I), or a salt, N-oxide, hydrate, or solvate thereof, in the preparation of a composition for inhibition of HSP90 activity in vitro or in vivo:
- R 2 is a group of formula (IA):
- the invention also includes:
- a pharmaceutical or veterinary composition comprising a compound of formula (I) above, together with a pharmaceutically or veterinarily acceptable carrier.
- a method of treatment of diseases or conditions mediated by excessive or inappropriate HSP90 activity in mammals which method comprises administering to the mammal an amount of a compound of formula (I) above effective to inhibit said HSP90 activity.
- (C 1 -C 6 )alkyl refers to a straight or branched chain alkyl radical having from 1 to 6 carbon atoms, including for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
- divalent (C 1 -C 6 )alkylene radical refers to a saturated hydrocarbon chain having from 1 to 6 carbon atoms and two unsatisfied valences.
- (C 1 -C 6 )alkenyl refers to a straight or branched chain alkenyl radical having from 2 to 6 carbon atoms and containing at least one double bond of E or Z configuration, including for example, ethenyl and allyl.
- divalent (C 2 -C 6 )alkenylene radical refers to a hydrocarbon chain having from 2 to 6 carbon atoms, at least one double bond, and two unsatisfied valences.
- cycloalkyl refers to a saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- cycloalkenyl refers to a carbocyclic radical having from 3-8 carbon atoms containing at least one double bond, and includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
- aryl refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical. Illustrative of such radicals are phenyl, biphenyl and napthyl.
- Carbocyclic refers to a cyclic radical whose ring atoms are all carbon, and includes monocyclic aryl, cycloalkyl, and cycloalkenyl radicals.
- heteroaryl refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O.
- Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.
- heterocyclyl or “heterocyclic” includes “heteroaryl” as defined above, and in particular refers to a mono-, bi- or tri-cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical.
- radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.
- substituted as applied to any moiety herein means substituted with at least one substituent selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, hydroxy(C 1 -C 6 )alkyl, mercapto, mercapto(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, halo (including fluoro and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, —COOR A , —COR A , —SO 2 R A , —CONH 2 , —SO 2 NH 2 , —CONHR A , —SO 2 NHR A , —CONR A R B , —SO 2 NR A R B , —NH 2 , —N
- salt includes base addition, acid addition and quaternary salts.
- Compounds of the invention which are acidic can form salts, including pharmaceutically or veterinarily acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-ethyl piperidine, dibenzylamine and the like.
- bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-ethyl piperidine, dibenzylamine and the like.
- Those compounds (I) which are basic can form salts, including pharmaceutically or veterinarily acceptable salts with inorganic acids, e.g.
- hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
- organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic and p-toluene sulphonic acids and the like.
- Some compounds with which the invention is concerned contain one or more actual or potential chiral centres because of the presence of asymmetric carbon atoms.
- the presence of several asymmetric carbon atoms gives rise to a number of diastereoisomers with R or S stereochemistry at each chiral centre.
- the invention includes the use of all such diastereoisomers and mixtures thereof.
- R 2 is a group of formula (IA):
- Ar 1 is an optionally substituted aryl or heteroaryl radical
- Alk 1 and Alk 2 are optionally substituted divalent C 1 -C 3 alkylene or C 2 -C 3 alkenylene radicals, m, p, r and s are independently 0 or 1
- Z is —O—, —S—, —(C ⁇ O)—, —(C ⁇ S)—, —SO 2 —, —C( ⁇ O)O—, —C( ⁇ O)NR A —, —C( ⁇ S)NR A —, —SO 2 NR A —, —NR A C( ⁇ O)—, —NR A SO 2 — or —NR A —
- R A is hydrogen or C 1 -C 6 alkyl
- Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical
- R 2 is optionally substituted aryl or heteroaryl.
- R 2 may be, for example, optionally substituted phenyl, 2- or 3-thienyl, 2- or 3-furanyl, or 2-, 3- or 4-Pyridinyl.
- R 2 is optionally substituted phenyl, for example where the optional substituents are selected from substituted methyl, ethyl, n- or isopropyl, methoxy, ethoxy, isopropoxy, chloro, or bromo, for example in the 4-position of the phenyl ring.
- m is 1, p, r and s are again each 0, and Q may be an optionally substituted carbocyclic or heterocyclic ring, for example phenyl, cyclohexyl, pyridyl, morpholino, piperidinyl, or piperazinyl ring.
- Q is a direct substituent in the optionally substituted Ar 1 ring.
- one or more of m, p, r and s may be 1, and Q may be hydrogen or an optionally substituted carbocyclic or heterocyclic ring.
- p and/or s may be 1 and r may be 0, so that Q is linked to Ar 1 by an alkylene or alkenylene radical, for example a C 1 -C 3 alkylene radical, which is optionally substituted.
- each of p, r, and s may be 1, in which cases, Q is linked to Ar 1 by an alkylene or alkenylene radical which is interrupted by the hetero atom-containing Z radical.
- p and s may be 0 and r may be 1, in which case Q is linked to Ar 1 via the hetero atom-containing Z radical.
- R 1 groups of the above types are present in the compounds of the Examples herein.
- R 3 is hydrogen or an optional substituent, as defined above. Presently it is preferred that R 3 be amino(NH 2 )
- R 4 is a carboxamide group
- examples include those of formula —CONR B (Alk) n R A wherein
- R 4 is a carboxylic ester group
- examples include those of formula —COOR C wherein R C is a C 1 -C 6 alkyl or C 2 -C 6 alkenyl group, for example methyl, ethyl, n- or iso-propyl, or allyl; or an optionally substituted aryl or heteroaryl group, for example optionally substituted phenyl, pyridyl or thiazolyl; or an optionally substituted aryl(C 1 -C 6 alkyl)- or heteroaryl(C 1 -C 6 alkyl)-group such as benzyl or pyridylmethyl; or an optionally substituted cycloalkyl group such as cyclopentyl or cyclohexyl.
- the compounds with which the invention is concerned are inhibitors of HSP90 and are useful in the treatment of diseases which are mediated by excessive or inappropriate HSP90 activity such as cancers; viral diseases such as Hepatitis C(HCV) (Waxman, 2002); Immunosupression such as in transplantation (Bijlmakers, 2000 and Yorgin, 2000); Anti-inflammatory diseases (Bucci, 2000) such as Rheumatoid arthritis, Asthma, MS, Type I Diabetes, Lupus, Psoriasis and Inflammatory Bowel Disease; Cystic fibrosis (Fuller, 2000); Angiogenesis-related diseases (Hur, 2002 and Kurebayashi, 2001): diabetic retinopathy, haemangiomas, psoriasis, endometriosis and tumour angiogenesis.
- HCV Hepatitis C
- HCV Hepatitis C(HCV)
- Immunosupression such as in transplantation (Bijlmakers, 2000 and Yorgin, 2000); Anti
- an Hsp90 inhibitor of the invention may protect normal cells against chemotherapy-induced toxicity and be useful in diseases where failure to undergo apoptosis is an underlying factor.
- Such an Hsp90 inhibitor may also be useful in diseases where the induction of a cell stress or heat shock protein response could be beneficial, for example, protection from hypoxia-ischemic injury due to elevation of Hsp70 in the heart (Hutter, 1996 and Trost, 1998) and brain (Plumier, 1997 and Rajder, 2000).
- Hsp90 inhibitor-induced increase in Hsp70 levels could also be useful in diseases where protein misfolding or aggregation is a major causal factor, for example, neurogenerative disorders such as scrapie/CJD, Huntingdon's and Alzheimer's (Sittler, 2001; Trazelt, 1995 and Winklhofer, 2001)”.
- a suitable dose for orally administrable formulations will usually be in the range of 0.1 to 3000 mg once, twice or three times per day, or the equivalent daily amount administered by infusion or other routes.
- optimum dose levels and frequency of dosing will be determined by clinical trials as is conventional in the art.
- the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
- the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
- Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
- the tablets may be coated according to methods well known in normal pharmaceutical practice.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
- suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
- emulsifying agents for example lecithin, sorbitan monooleate, or acacia
- non-aqueous vehicles which may include edible oils
- almond oil fractionated coconut oil
- oily esters such as glycerine, propylene
- the drug may be made up into a cream, lotion or ointment.
- Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
- the active ingredient may also be administered parenterally in a sterile medium.
- the drug can either be suspended or dissolved in the vehicle.
- adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
- 6-Amino-4-phenyl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile leg was added to a freshly prepared solution of NaOEt (3 eq) in EtOH. Ethylbromoacetate (1 eq) was added and stirred for a few minutes at room temperature during which time, a thick solid precipitated out of solution. The reaction mixture was heated at 80° C. for 1.5 hours, after which time the solution was cooled back to room temperature. The resulting precipitate, 3,6-diamino-5-cyano-4-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester, was collected by vacuum filtration.
- the compound of Example 1 had activity in the “A” range when tested in the fluorescence polarisation assay described below.
- Additional compounds were either procured from commercially available sources, or synthesised by methods analogous to that of Example 1. Compounds procured from commercial sources may also be synthesised by the method of Example 1. Additional compounds are identified and characterised by mass ion data in the following Table. The source of the compound is identified in the final column, or the compound by the following
- the penultimate column of the table shows the result obtained in the fluorescence polarisation assay described below
- Fluorescence polarization ⁇ also known as fluorescence anisotropy ⁇ measures the rotation of a fluorescing species in solution, where the larger molecule the more polarized the fluorescence emission. When the fluorophore is excited with polarized light, the emitted light is also polarized. The molecular size is proportional to the polarization of the fluorescence emission.
- HSP90 full-length human, full-length yeast or N-terminal domain HSP90 ⁇ and the anisotropy ⁇ rotation of the probe:protein complex ⁇ is measured.
- Test compound is added to the assay plate, left to equilibrate and the anisotropy measured again. Any change in anisotropy is due to competitive binding of compound to HSP90, thereby releasing probe.
- Chemicals are of the highest purity commercially available and all aqueous solutions are made up in AR water.
Abstract
The use of compounds of formula (I) in therapy, particularly for the treatment of a disorder mediated by excessive or inappropriate HSP90 activity formula (I), wherein R2 is a group of formula (IA):
—(Ar1)m-(Alk1)p-(Z)r-(Alk2)S-Q (IA)
Ar1, Alk1, Z, Alk2 and Q being as defined in the specification; m, p, r and s are independently 0 or 1; R3 is hydrogen, an optional substituent, or an optionally substituted (C1-C6)alkyl, aryl or heteroaryl radical; and R4 is a carboxylic ester, carboxamide or sulfonamide group; or a salt, N-oxide, hydrate, or solvate thereof.
Description
- This invention relates to substituted bicyclic thieno[2,3-d]pyridine (herein referred to as ‘pyridothiophene’) compounds having HSP90 inhibitory activity, to the use of such compounds in medicine, in relation to diseases which are mediated by excessive or inappropriate HSP90 activity such as cancers, and to pharmaceutical compositions containing such compounds.
- Molecular chaperones maintain the appropriate folding and conformation of proteins and are crucial in regulating the balance between protein synthesis and degradation. They have been shown to be important in regulating many important cellular functions, such as cell proliferation and apoptosis (Jolly and Morimoto, 2000; Smith et al., 1998; Smith, 2001).
- Exposure of cells to a number of environmental stresses, including heat shock, alcohols, heavy metals and oxidative stress, results in the cellular accumulation of a number of chaperones, commonly known as heat shock proteins (HSPs). Induction of HSPs protects the cell against the initial stress insult, enhances recovery and leads to maintenance of a stress tolerant state. It has also become clear, however, that certain HSPs may also play a major molecular chaperone role under normal, stress-free conditions by regulating the correct folding, degradation, localization and function of a growing list of important cellular proteins.
- A number of multigene families of HSPs exist, with individual gene products varying in cellular expression, function and localization. They are classified according to molecular weight, e.g., HSP70, HSP90, and HSP27. Several diseases in humans can be acquired as a result of protein misfolding (reviewed in Tytell et al., 2001; Smith et al., 1998). Hence the development of therapies which disrupt the molecular chaperone machinery may prove to be beneficial. In some conditions (e.g., Alzheimer's disease, prion diseases and Huntington's disease), misfolded proteins can cause protein aggregation resulting in neurodegenerative disorders. Also, misfolded proteins may result in loss of wild type protein function, leading to deregulated molecular and physiological functions in the cell.
- HSPs have also been implicated in cancer. For example, there is evidence of differential expression of HSPs which may relate to the stage of tumour progression (Martin et al., 2000; Conroy et al., 1996; Kawanishi et al., 1999; Jameel et al., 1992; Hoang et al., 2000; Lebeau et al., 1991). As a result of the involvement of HSP90 in various critical oncogenic pathways and the discovery that certain natural products with anticancer activity are targeting this molecular chaperone, the fascinating new concept has been developed that inhibiting HSP function may be useful in the treatment of cancer. The first molecular chaperone inhibitor is currently undergoing clinical trials.
- HSP90 constitutes about 1-2% of total cellular protein, and is usually present in the cell as a dimer in association with one of a number of other proteins (see, e.g., Pratt, 1997). It is essential for cell viability and it exhibits dual chaperone functions (Young et al., 2001). It plays a key role in the cellular stress response by interacting with many proteins after their native conformation has been altered by various environmental stresses, such as heat shock, ensuring adequate protein folding and preventing non-specific aggregation (Smith et al., 1998). In addition, recent results suggest that HSP90 may also play a role in buffering against the effects of mutation, presumably by correcting the inappropriate folding of mutant proteins (Rutherford and Lindquist, 1998). However, HSP90 also has an important regulatory role. Under normal physiological conditions, together with its endoplasmic reticulum homologue GRP94, HSP90 plays a housekeeping role in the cell, maintaining the conformational stability and maturation of several key client proteins. These can be subdivided into three groups: (a) steroid hormone receptors, (b) Ser/Thr or tyrosine kinases (e.g., ERBB2, RAF-1, CDK4, and LCK), and (c) a collection of apparently unrelated proteins, e.g., mutant p53 and the catalytic subunit of telomerase hTERT. All of these proteins play key regulatory roles in many physiological and biochemical processes in the cell. New HSP90 client proteins are continuously being identified.
- The highly conserved HSP90 family in humans consists of four genes, namely the cytosolic HSP90a and HSP908 isoforms (Hickey et al., 1989), GRP94 in the endoplasmic reticulum (Argon et al., 1999) and FISP75/TRAP1 in the mitochondrial matrix (Felts et al., 2000). It is thought that all the family members have a similar mode of action, but bind to different client proteins depending on their localization within the cell. For example, ERBB2 is known to be a specific client protein of GRP94 (Argon et al., 1999) and type 1 tumour necrosis factor receptor (INFR1) and RB have both been shown to be clients of TRAP1 (Song et al., 1995; Chen et al., 1996).
- HSP90 participates in a series of complex interactions with a range of client and regulatory proteins (Smith, 2001). Although the precise molecular details remain to be elucidated, biochemical and X-ray crystallographic studies (Prodromou et al., 1997; Stebbins et al., 1997) carried out over the last few years have provided increasingly detailed insights into the chaperone function of HSP90.
- Following earlier controversy on this issue, it is now clear that HSP90 is an ATP-dependent molecular chaperone (Prodromou et al, 1997), with dimerization of the nucleotide binding domains being essential for ATP hydrolysis, which is in turn essential for chaperone function (Prodromou et al, 2000a). Binding of ATP results in the formation of a toroidal dimer structure in which the N terminal domains are brought into closer contact with each other resulting in a conformational switch known as the ‘clamp mechanism’ (Prodromou and Pearl, 2000b).
- The first class of HSP90 inhibitors to be discovered was the benzoquinone ansamycin class, which includes the compounds herbimycin A and geldanamycin. They were shown to reverse the malignant phenotype of fibroblasts transformed by the v-Src oncogene (Uehara et al., 1985), and subsequently to exhibit potent antitumour activity in both in vitro (Schulte et al., 1998) and in vivo animal models (Supko et al., 1995).
- Immunoprecipitation and affinity matrix studies have shown that the major mechanism of action of geldanamycin involves binding to HSP90 (Whitesell et al., 1994; Schulte and Neckers, 1998). Moreover, X-ray crystallographic studies have shown that geldanamycin competes at the ATP binding site and inhibits the intrinsic ATPase activity of HSP90 (Prodromou et al., 1997; Panaretou et al., 1998). This in turn prevents the formation of mature multimeric HSP90 complexes capable of chaperoning client proteins. As a result, the client proteins are targeted for degradation via the ubiquitin proteasome pathway. 17-Allylamino, 17-demethoxygeldanamycin (17AAG) retains the property of HSP90 inhibition resulting in client protein depletion and antitumour activity in cell culture and xenograft models (Schulte et al, 1998; Kelland et al, 1999), but has significantly less hepatotoxicity than geldanamycin (Page et al, 1997). 17AAG is currently being evaluated in Phase I clinical trials.
- Radicicol is a macrocyclic antibiotic shown to reverse the malignant phenotype of v-Src and v-Ha-Ras transformed fibroblasts (Kwon et al, 1992; Zhao et al, 1995). It was shown to degrade a number of signalling proteins as a consequence of HSP90 inhibition (Schulte et al., 1998). X-ray crystallographic data confirmed that radicicol also binds to the N terminal domain of HSP90 and inhibits the intrinsic ATPase activity (Roe et al., 1998). Radicicol lacks antitumour activity in vivo due to the unstable chemical nature of the compound.
- Coumarin antibiotics are known to bind to bacterial DNA gyrase at an ATP binding site homologous to that of the HSP90. The coumarin, novobiocin, was shown to bind to the carboxy terminus of HSP90, i.e., at a different site to that occupied by the benzoquinone ansamycins and radicicol which bind at the N-terminus (Marcu et al., 2000b). However, this still resulted in inhibition of HSP90 function and degradation of a number of HSP90-chaperoned signalling proteins (Marcu et al., 2000a). Geldanamcyin cannot bind HSP90 subsequent to novobiocin; this suggests that some interaction between the N and C terminal domains must exist and is consistent with the view that both sites are important for HSP90 chaperone properties.
- A purine-based HSP90 inhibitor, PU3, has been shown to result in the degradation of signalling molecules, including ERBB2, and to cause cell cycle arrest and differentiation in breast cancer cells (Chiosis et al., 2001).
- Due to its involvement in regulating a number of signalling pathways that are crucially important in driving the phenotype of a tumour, and the discovery that certain bioactive natural products exert their effects via HSP90 activity, the molecular chaperone HSP90 is currently being assessed as a new target for anticancer drug development (Neckers et al., 1999).
- The predominant mechanism of action of geldanamycin, 17AAG, and radicicol involves binding to HSP90 at the ATP binding site located in the N-terminal domain of the protein, leading to inhibition of the intrinsic ATPase activity of HSP90 (see, e.g., Prodromou et al., 1997; Stebbins et al., 1997; Panaretou et al., 1998).
- Inhibition of HSP90 ATPase activity prevents recruitment of co-chaperones and encourages the formation of a type of HSP90 heterocomplex from which these client proteins are targeted for degradation via the ubiquitin proteasome pathway (see, e.g., Neckers et al., 1999; Kelland et al., 1999).
- Treatment with HSP90 inhibitors leads to selective degradation of important proteins involved in cell proliferation, cell cycle regulation and apoptosis, processes which are fundamentally important in cancer.
- Inhibition of HSP90 function has been shown to cause selective degradation of important signalling proteins involved in cell proliferation, cell cycle regulation and apoptosis, processes which are fundamentally important and which are commonly deregulated in cancer (see, e.g., Hostein et al., 2001). An attractive rationale for developing drugs against this target for use in the clinic is that by simultaneously depleting proteins associated with the transformed phenotype, one may obtain a strong antitumour effect and achieve a therapeutic advantage against cancer versus normal cells. These events downstream of HSP90 inhibition are believed to be responsible for the antitumour activity of HSP90 inhibitors in cell culture and animal models (see, e.g., Schulte et al., 1998; Kelland et al., 1999).
- The present invention relates to the use of a class of substituted thieno[2,3-d]pyridine compounds (referred to herein as pyridothiophenes) as HSP90 inhibitors, for example for inhibition of cancer cell proliferation. A core pyridothiophene ring system with amino, cyano and aromatic substitution on the pyrido ring are principle characterising features of the compounds with which the invention is concerned.
- The present invention provides the use of a compound of formula (I), or a salt, N-oxide, hydrate, or solvate thereof, in the preparation of a composition for inhibition of HSP90 activity in vitro or in vivo:
- wherein
R2 is a group of formula (IA): -
—(Ar1)m-(Alk1)p-(Z)r-(Alk2)s-Q (IA) -
- wherein in any compatible combination
- Ar1 is an optionally substituted aryl or heteroaryl radical,
- Alk1 and Alk2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals,
- m, p, r and s are independently 0 or 1,
- Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO2—, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and
- Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical;
R3 is hydrogen, an optional substituent, or an optionally substituted (C1-C6)alkyl, aryl or heteroaryl radical; and
R4 is a carboxylic ester, carboxamide or sulfonamide group.
- wherein in any compatible combination
- The invention also includes:
- (i) A pharmaceutical or veterinary composition comprising a compound of formula (I) above, together with a pharmaceutically or veterinarily acceptable carrier.
(ii). A method of treatment of diseases or conditions mediated by excessive or inappropriate HSP90 activity in mammals which method comprises administering to the mammal an amount of a compound of formula (I) above effective to inhibit said HSP90 activity. - As used herein:
-
- the term “carboxyl group” refers to a group of formula —COOH;
- the term “carboxyl ester group” refers to a group of formula —COOR, wherein R is a radical actually or notionally derived from the hydroxyl compound ROH; and
- the term “carboxamide group” refers to a group of formula —CONRaRb, wherein —NRaRb is a primary or secondary (including cyclic) amino group actually or notionally derived from ammonia or the amine HNRaRb.
- the term “sulfonamide group” refers to a group of formula —SO2NRaRb, wherein —NRaRb is a primary or secondary (including cyclic) amino group actually or notionally derived from ammonia or the amine HNRaRb
- As used herein, the term “(C1-C6)alkyl” refers to a straight or branched chain alkyl radical having from 1 to 6 carbon atoms, including for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
- As used herein the term “divalent (C1-C6)alkylene radical” refers to a saturated hydrocarbon chain having from 1 to 6 carbon atoms and two unsatisfied valences.
- As used herein, the term “(C1-C6)alkenyl” refers to a straight or branched chain alkenyl radical having from 2 to 6 carbon atoms and containing at least one double bond of E or Z configuration, including for example, ethenyl and allyl.
- As used herein the term “divalent (C2-C6)alkenylene radical” refers to a hydrocarbon chain having from 2 to 6 carbon atoms, at least one double bond, and two unsatisfied valences.
- As used herein the term “cycloalkyl” refers to a saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- As used herein the term “cycloalkenyl” refers to a carbocyclic radical having from 3-8 carbon atoms containing at least one double bond, and includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
- As used herein the term “aryl” refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical. Illustrative of such radicals are phenyl, biphenyl and napthyl.
- As used herein the term “carbocyclic” refers to a cyclic radical whose ring atoms are all carbon, and includes monocyclic aryl, cycloalkyl, and cycloalkenyl radicals.
- As used herein the term “heteroaryl” refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O. Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.
- As used herein the unqualified term “heterocyclyl” or “heterocyclic” includes “heteroaryl” as defined above, and in particular refers to a mono-, bi- or tri-cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical. Illustrative of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.
- Unless otherwise specified in the context in which it occurs, the term “substituted” as applied to any moiety herein means substituted with at least one substituent selected from (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, mercapto, mercapto(C1-C6)alkyl, (C1-C6)alkylthio, halo (including fluoro and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, —COORA, —CORA, —SO2RA, —CONH2, —SO2NH2, —CONHRA, —SO2NHRA, —CONRARB, —SO2NRARB, —NH2, —NHRA, —NRARB, —OCONH2, —OCONHRA, —OCONRARB, —NHCORA, —NHCOORA, —NRBCOORA, —NHSO2ORA, —NRBSO2ORA, —NHCONH2, —NRACONH2, —NHCONHRB, —NRACONHRB, —NHCONRARB, or —NRACONRARB wherein RA and RB are independently a (C1-C6)alkyl group. The term “optional substituent” means one of the foregoing substituent groups.
- As used herein the term “salt” includes base addition, acid addition and quaternary salts. Compounds of the invention which are acidic can form salts, including pharmaceutically or veterinarily acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-ethyl piperidine, dibenzylamine and the like. Those compounds (I) which are basic can form salts, including pharmaceutically or veterinarily acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic and p-toluene sulphonic acids and the like.
- Some compounds with which the invention is concerned contain one or more actual or potential chiral centres because of the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms gives rise to a number of diastereoisomers with R or S stereochemistry at each chiral centre. The invention includes the use of all such diastereoisomers and mixtures thereof.
- As stated, R2 is a group of formula (IA):
-
—(Ar1)m-(Alk1)p-(Z)r-(Alk2)s-Q (IA) - wherein in any compatible combination Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1 and Alk2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals, m, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO2—, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical;
- In a simple subclass of compounds with which the invention is concerned, m is 1 and each of p, r and s is 0, and Q is hydrogen, so that R2 is optionally substituted aryl or heteroaryl. In such cases, R2 may be, for example, optionally substituted phenyl, 2- or 3-thienyl, 2- or 3-furanyl, or 2-, 3- or 4-Pyridinyl. Currently preferred are compounds wherein R2 is optionally substituted phenyl, for example where the optional substituents are selected from substituted methyl, ethyl, n- or isopropyl, methoxy, ethoxy, isopropoxy, chloro, or bromo, for example in the 4-position of the phenyl ring.
- In other simple structures, m is 1, p, r and s are again each 0, and Q may be an optionally substituted carbocyclic or heterocyclic ring, for example phenyl, cyclohexyl, pyridyl, morpholino, piperidinyl, or piperazinyl ring. In such cases, Q is a direct substituent in the optionally substituted Ar1 ring.
- In more complex structures with which the invention is concerned, one or more of m, p, r and s may be 1, and Q may be hydrogen or an optionally substituted carbocyclic or heterocyclic ring. For example, p and/or s may be 1 and r may be 0, so that Q is linked to Ar1 by an alkylene or alkenylene radical, for example a C1-C3 alkylene radical, which is optionally substituted. In other cases each of p, r, and s may be 1, in which cases, Q is linked to Ar1 by an alkylene or alkenylene radical which is interrupted by the hetero atom-containing Z radical. In still other cases, p and s may be 0 and r may be 1, in which case Q is linked to Ar1 via the hetero atom-containing Z radical.
- Specific examples of R1 groups of the above types are present in the compounds of the Examples herein.
- R3 is hydrogen or an optional substituent, as defined above. Presently it is preferred that R3 be amino(NH2)
- When R4 is a carboxamide group, examples include those of formula —CONRB(Alk)nRA wherein
-
- Alk is a divalent alkylene, alkenylene or alkynylene radical, for example a —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH═CH—, or —CH2CCCH2-radical, and the Alk radical may be optionally substituted,
- n is 0 or 1,
- RB is hydrogen or a C1-C6 alkyl or C2-C6 alkenyl group, for example methyl, ethyl, n- or iso-propyl, or allyl, (most preferably hydrogen)
- RA is hydroxy or optionally substituted carbocyclic, for example hydroxy and/or chloro-substituted phenyl and 3,4 methylenedioxyphenyl; or heterocyclyl, for example pyridyl, furyl, thienyl, N-piperazinyl, or N-morpholinyl any of which heterocyclic rings may be substituted,
- or RA and RB taken together with the nitrogen to which they are attached form an N-heterocyclic ring which may optionally contain one or more additional hetero atoms selected from O, S and N, and which may optionally be substituted on one or more ring C or N atoms, examples of such N-heterocyclic rings including morpholino, piperidinyl, piperazinyl and N-phenylpiperazinyl.
- When R4 is a carboxylic ester group, examples include those of formula —COORC wherein RC is a C1-C6 alkyl or C2-C6 alkenyl group, for example methyl, ethyl, n- or iso-propyl, or allyl; or an optionally substituted aryl or heteroaryl group, for example optionally substituted phenyl, pyridyl or thiazolyl; or an optionally substituted aryl(C1-C6 alkyl)- or heteroaryl(C1-C6 alkyl)-group such as benzyl or pyridylmethyl; or an optionally substituted cycloalkyl group such as cyclopentyl or cyclohexyl.
- Specific compounds with which the invention is concerned include those of the Examples.
- Compounds with which the invention is concerned may be prepared by literature methods, such as those of the preparative Examples herein, and methods analogous thereto. For example the following general reaction scheme can be employed:
- Starting material are either available commercially or can be made according to literature methods. Subsequent reactions may be carried out on R2, R3 or R4 to prepare additional compounds of formula (I)
- The compounds with which the invention is concerned are inhibitors of HSP90 and are useful in the treatment of diseases which are mediated by excessive or inappropriate HSP90 activity such as cancers; viral diseases such as Hepatitis C(HCV) (Waxman, 2002); Immunosupression such as in transplantation (Bijlmakers, 2000 and Yorgin, 2000); Anti-inflammatory diseases (Bucci, 2000) such as Rheumatoid arthritis, Asthma, MS, Type I Diabetes, Lupus, Psoriasis and Inflammatory Bowel Disease; Cystic fibrosis (Fuller, 2000); Angiogenesis-related diseases (Hur, 2002 and Kurebayashi, 2001): diabetic retinopathy, haemangiomas, psoriasis, endometriosis and tumour angiogenesis. Also an Hsp90 inhibitor of the invention may protect normal cells against chemotherapy-induced toxicity and be useful in diseases where failure to undergo apoptosis is an underlying factor. Such an Hsp90 inhibitor may also be useful in diseases where the induction of a cell stress or heat shock protein response could be beneficial, for example, protection from hypoxia-ischemic injury due to elevation of Hsp70 in the heart (Hutter, 1996 and Trost, 1998) and brain (Plumier, 1997 and Rajder, 2000). An Hsp90 inhibitor-induced increase in Hsp70 levels could also be useful in diseases where protein misfolding or aggregation is a major causal factor, for example, neurogenerative disorders such as scrapie/CJD, Huntingdon's and Alzheimer's (Sittler, 2001; Trazelt, 1995 and Winklhofer, 2001)”.
- It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the causative mechanism and severity of the particular disease undergoing therapy. In general, a suitable dose for orally administrable formulations will usually be in the range of 0.1 to 3000 mg once, twice or three times per day, or the equivalent daily amount administered by infusion or other routes. However, optimum dose levels and frequency of dosing will be determined by clinical trials as is conventional in the art.
- The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
- For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
- The active ingredient may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
- The following examples illustrate the preparation and activities of specific compounds with which the invention is concerned.
-
- Malonitrile (1 eq) was dissolved in EtOH with stirring under a N2 atmosphere. Benzaldehyde (1.1 eq) was added followed by catalytic N-methylmorpholine. The mixture was stirred at 50° C. for 30 minutes, after which time the solution had produced a heavy precipitate. The reaction was allowed to cool to room temperature and 2-benzylidene-malononitrile was collected by vacuum filtration.
- LC retention time=2.416 min [M+H]+ not observed
- 2-Benzylidene-malononitrile (1 eq) was dissolved with stirring in EtOH and cyanothioacetamide (1 eq) was added. N-Methylmorpholine (2 eq) was added and all was heated at reflux overnight under a N2 atmosphere. Allowed to cool to room temperature, and the resulting precipitate, 6-amino-4-phenyl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile, was collected by vacuum filtration. LC retention time=2.04 min [M+H]+ 253.1
- 6-Amino-4-phenyl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile (leg) was added to a freshly prepared solution of NaOEt (3 eq) in EtOH. Ethylbromoacetate (1 eq) was added and stirred for a few minutes at room temperature during which time, a thick solid precipitated out of solution. The reaction mixture was heated at 80° C. for 1.5 hours, after which time the solution was cooled back to room temperature. The resulting precipitate, 3,6-diamino-5-cyano-4-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester, was collected by vacuum filtration.
- LC retention time=2.603 min [M+H]+ 339.1
- 3,6-Diamino-5-cyano-4-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester was suspended in EtOH and 3M NaOH (aq) (3 eq) was added. The suspension was heated to reflux and dissolution occurred. Allowed to cool to room temperature on completion and the reaction mixture was concentrated in vacuo. The residue was taken up in water and acidified by addition of 1M HCl (aq). The resulting precipitate, 3,6-diamino-5-cyano-4-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid, was collected by vacuum filtration. LC retention time=2.098 min [M+H]+ 311.1
- 3,6-Diamino-5-cyano-4-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid (leg) was taken up in DMF with stirring and HATU (1.1 eq), excess 2M methanolic ethylamine and DIPEA (3 eq) were added. Stirred overnight at room temperature. The DMF was removed by evaporation and the residue was dissolved in DCM. This was washed with 1M HCl (aq), saturated NaHCO3 (aq) and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then purified by column chromatography, eluting with 0.5% MeOH/DCM to give 3,6-diamino-5-cyano-4-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid ethylamide.
- LC retention time=2.259 min [M+H]+ 338.1
- The compound of Example 1 had activity in the “A” range when tested in the fluorescence polarisation assay described below.
- Additional compounds were either procured from commercially available sources, or synthesised by methods analogous to that of Example 1. Compounds procured from commercial sources may also be synthesised by the method of Example 1. Additional compounds are identified and characterised by mass ion data in the following Table. The source of the compound is identified in the final column, or the compound by the following
- “Synth” compound synthesised de novo.
“Specs” compound purchased from: Specs, Fleminglaan 16, 2289 CP Rijswijk, The Netherlands
“IBS” compound purchased from: InterBioScreen Ltd., 121019 Moscow, P.O. Box 218, Russia
“ASI” compound purchased from: ASINEX Ltd, 6 Schukinskaya Street, Moscow 123182, Russia - The penultimate column of the table shows the result obtained in the fluorescence polarisation assay described below
-
Hsp90 FP Example Structure MH+ IC50 Source 2 442 B Specs 3 458 B Specs 4 389 B IBS 5 435 B IBS 6 352 A IBS 7 344 A IBS 8 354 A ASI 9 465 B IBS 10 370 B IBS 11 352 B Synth 12 400 B Synth 13 366 B Synth 14 324 A Synth 15 382 A Synth 16 393 B Synth 17 395 B Synth 18 450 B Synth 19 437 B Synth 20 380 B Synth 21 422 B Synth 22 367 A Synth 23 381 B Synth 24 354 B Synth 25 310 B Synth 26 352 B Synth 27 383 B Synth - Fluorescence polarization {also known as fluorescence anisotropy} measures the rotation of a fluorescing species in solution, where the larger molecule the more polarized the fluorescence emission. When the fluorophore is excited with polarized light, the emitted light is also polarized. The molecular size is proportional to the polarization of the fluorescence emission.
- The fluoroscein-labelled probe—RBT0045864-FAM—
- binds to HSP90 {full-length human, full-length yeast or N-terminal domain HSP90} and the anisotropy {rotation of the probe:protein complex} is measured.
- Test compound is added to the assay plate, left to equilibrate and the anisotropy measured again. Any change in anisotropy is due to competitive binding of compound to HSP90, thereby releasing probe.
- Chemicals are of the highest purity commercially available and all aqueous solutions are made up in AR water.
- 1) Costar 96-well black assay plate #3915
- 2) Assay buffer of (a) 100 mM Tris pH7.4; (b) 20 mM KCl; (c) 6 mM MgCl2. Stored at room temperature.
- 3) BSA (bovine serum albumen) 10 mg/ml (New England Biolabs # B9001S)
- 4) 20 mM probe in 100% DMSO stock concentration. Stored in the dark at RT. Working concentration is 200 nM diluted in AR water and stored at 4° C. Final concentration in assay 80 nM.
- 5) E. coli expressed human full-length HSP90 protein, purified >95% (see, e.g., Panaretou et al., 1998) and stored in 50 μL aliquots at −80° C.
-
-
- 1) Add 100 μl 1× buffer to wells 11A and 12A (=FP BLNK)
- 2) Prepare assay mix—all reagents are kept on ice with a lid on the bucket as the probe is light-sensitive.
-
I. Final Concn 1x Hsp90 FP Buffer 10 ml 1x BSA 10 mg/ml (NEB) 5.0 μl 5 μg/ml Probe 200 μM 4.0 μl 80 nM Human full-length Hsp90 6.25 μl 200 nM -
- 3) Aliquot 100 μl assay mix to all other wells
- 4) Seal plate and leave in dark at room temp for 20 minutes to equilibrate
-
-
- 1) In a clear 96-well v-bottom plate—{# VWR 007/0081257} add 10 μl 100% DMSO to wells B1 to H11
- 2) To wells A1 to A11 add 17.5 μl 100% DMSO
- 3) Add 2.5 μl cpd to A1. This gives 2.5 mM {50×} stock cpd—assuming cpds 20 mM.
- 4) Repeat for wells A2 to A10. Control in columns 11 and 12.
- 5) Transfer 5 μl from row A to row B—not column 12. Mix well.
- 6) Transfer 5 μl from row B to row C. Mix well.
- 7) Repeat to row G.
- 8) Do not add any compound to row H—this is the 0 row.
- 9) This produces a 1×3 dilution series from 50 μM to 0.07 μM.
- 10) In well B12 prepare 20 μl of 100 μM standard compound.
- 11) After first incubation the assay plate is read on a Fusion™ a-FP plate reader (Packard BioScience, Pangbourne, Berkshire, UK).
- 12) After the first read, 2 μl of diluted compound is added to each well for columns 1 to 10. In column 11 {provides standard curve} only add compound B11-H11. Add 2 μl of 100 mM standard cpd to wells B12-H12 {is positive control}
- 13) The Z′ factor is calculated from zero controls and positive wells. It typically gives a value of 0.7-0.9.
- The compounds tested in the above assay were assigned to one of two activity ranges, namely A=<10 μM; B=>10 μM, and those assignments are reported above.
- A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure.
- Argon Y and Simen B B. 1999 “Grp94, an ER chaperone with protein and peptide binding properties”, Semin. Cell Dev. Biol., Vol. 10, pp. 495-505.
- Bijlmakers M-JJE, Marsh M. 2000 “Hsp90 is essential for the synthesis and subsequent membrane association, but not the maintenance, of the Src-kinase p56lck”, Molecular Biology of the Cell, Vol. 11(5), pp. 1585-1595.
- Bucci M; Roviezzo F; Cicala C; Sessa W C, Cirino G. 2000 “Geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) mediated signal transduction has anti-inflammatory effects and interacts with glucocorticoid receptor in vivo”, Brit. J. Pharmacol., Vol 131(1), pp. 13-16.
- Chen C-F, Chen Y, Dai K D, Chen P-L, Riley D J and Lee W-H. 1996 “A new member of the hsp90 family of molecular chaperones interacts with the retinoblastoma protein during mitosis and after heat shock”, Mol. Cell. Biol., Vol. 16, pp. 4691-4699.
- Chiosis G, Timaul M N, Lucas B, Munster P N, Zheng F F, Sepp-Lozenzino L and Rosen N. 2001 “A small molecule designed to bind to the adenine nucleotide pocket of HSP90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells”, Chem. Biol., Vol. 8, pp. 289-299.
- Conroy S E and Latchman D S. 1996 “Do heat shock proteins have a role in breast cancer?”, Brit. J. Cancer, Vol. 74, pp. 717-721.
- Felts S J, Owen B A L, Nguyen P, Trepel J, Donner D B and Toft D O. 2000 “The HSP90-related protein TRAP1 is a mitochondrial protein with distinct functional properties”, J. Biol. Chem., Vol. 5, pp. 3305-3312.
- Fuller W, Cuthbert A W. 2000 “Post-translational disruption of the delta F508 cystic fibrosis transmembrane conductance regulator (CFTR)-molecular Chaperone complex with geldanamycin stabilizes delta F508 CFTR in the rabbit reticulocyte lysate”, J. Biol. Chem.; Vol 275(48), pp. 37462-37468.
- Hickey E, Brandon S E, Smale G, Lloyd D and Weber L A. 1999 “Sequence and regulation of a gene encoding a human 89-kilodalton heat shock protein”, Mol. Cell. Biol., Vol. 9, pp. 2615-2626.
- Hoang A T, Huang J, Rudra-Gonguly N, Zheng J, Powell W C, Rabindron S K, Wu C and Roy-Burman P. 2000 “A novel association between the human heat shock transcription factor I (HSF1) and prostate adenocarcinoma, Am. J. Pathol., Vol. 156, pp. 857-864.
- Hostein I, Robertson D, Di Stefano F, Workman P and Clarke P A. 2001 “Inhibition of signal transduction by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in cytostasis and apoptosis”, Cancer Res., Vol. 61, pp. 4003-4009.
- Hur E, Kim H-H, Choi S M, Kim J H, Yim S, Kwon H J, Choi Y, Kim D K, Lee M-O, Park H. 2002 “Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1α/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol”, Mol. Pharmacol., Vol 62(5), pp. 975-982.
- Hutter et al, 1996, Circulation, Vol. 94, pp. 1408.
- Jameel A, Skilton R A, Campbell T A, Chander S K, Coombes R C and Luqmani Y A. 1992 “Clinical and biological significance of HSP89a in human breast cancer”, Int. J. Cancer, Vol. 50, pp. 409-415.
- Jolly C and Morimoto R I. 2000 “Role of the heat shock response and molecular chaperones in oncogenesis and cell death”, J. Natl. Cancer Inst., Vol. 92, pp. 1564-1572.
- Kawanishi K, Shiozaki H, Doki Y, Sakita I, Inoue M, Yano M, Tsujinata T, Shamma A and Monden M. 1999 “Prognostic significance of heat shock proteins 27 and 70 in patients with squamous cell carcinoma of the esophagus”, Cancer, Vol. 85, pp. 1649-1657.
- Kelland L R, Abel G, McKeage M J, Jones M, Goddard P M, Valenti M, Murrer B A and Harrap K R. 1993 “Preclinical antitumour evaluation of bis-acetalo-amino-dichloro-cyclohexylamine platinum (IV): an orally active platinum drug”, Cancer Research, Vol. 53, pp. 2581-2586.
- Kelland L R, Sharp S Y, Rogers P M, Myers T G and Workman P. 1999 “DT-diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90”, J. Natl. Cancer Inst., Vol. 91, pp. 1940-1949.
- Kurebayashi J, Otsuki T, Kurosumi M, Soga S, Akinaga S, Sonoo, H. 2001 “A radicicol derivative, KF58333, inhibits expression of hypoxia-inducible factor-1α and vascular endothelial growth factor, angiogenesis and growth of human breast cancer xenografts”, Jap. J. Cancer Res., Vol 92(12), 1342-1351.
- Kwon H J, Yoshida M, Abe K, Horinouchi S and Bepple T. 1992 “Radicicol, an agent inducing the reversal of transformed phentoype of src-transformed fibroblasts, Biosci., Biotechnol., Biochem., Vol. 56, pp. 538-539.
- Lebeau J, Le Cholony C, Prosperi M T and Goubin G. 1991 “Constitutive overexpression of 89 kDa heat shock protein gene in the HBL100 mammary cell line converted to a tumorigenic phenotype by the EJ/T24 Harvey-ras oncogene”, Oncogene, Vol. 6, pp. 1125-1132.
- Marcu M G, Chadli A, Bouhouche I, Catelli M and Neckers L. 2000a “The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone”, J. Biol. Chem., Vol. 275, pp. 37181-37186.
- Marcu M G, Schulte T W and Neckers L. 2000b “Novobiocin and related coumarins and depletion of heat shock protein 90-dependent signaling proteins”, J. Natl. Cancer Inst., Vol. 92, pp. 242-248.
- Martin K J, Kritzman B M, Price L M, Koh B, Kwan C P, Zhang X, MacKay A, O'Hare M J, Kaelin C M, Mutter G L, Pardee A B and Sager R. 2000 “Linking gene expression patterns to therapeutic groups in breast cancer”, Cancer Res., Vol. 60, pp. 2232-2238.
- Neckers L, Schulte T W and Momnaaugh E. 1999 “Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity”, Invest. New Drugs, Vol. 17, pp. 361-373,
- Page J, Heath J, Fulton R, Yalkowsky E, Tabibi E, Tomaszewski J, Smith A and Rodman L. 1997 “Comparison of geldanamycin (NSC-122750) and 17-allylaminogeldanamycin (NSC-330507D) toxicity in rats”, Proc. Am. Assoc. Cancer Res., Vol. 38, pp. 308.
- Panaretou B, Prodromou C, Roe S M, O'Brien R, Ladbury J E, Piper P W and Pearl L H. 1998 “ATP binding and hydrolysis are essential to the function of the HSP90 molecular chaperone in vivo”, EMBO J., Vol. 17, pp. 4829-4836.
- Plumier et al, 1997, Cell. Stress Chap., Vol. 2, pp. 162
- Pratt W B. 1997 “The role of the HSP90-based chaperone system in signal transduction by nuclear receptors and receptors signalling via MAP kinase”, Annu. Rev. Pharmacol. Toxicol., Vol. 37, pp. 297-326.
- Prodromou C and Pearl L H. 2000a “Structure and in vivo function of HSP90”, Curr. Opin. Struct. Biol., Vol. 10, pp. 46-51.
- Prodromou C, Roe S M, O'Brien R, Ladbury J E, Piper P W and Pearl L H. 1997 “Identification and structural characterization of the ATP/ADP-binding site in the HSP90 molecular chaperone”, Cell, Vol. 90, pp. 65-75.
- Prodromou C, Panaretou B, Chohan S, Siligardi G, O'Brien R, Ladbury J E, Roe S M, Piper P W and Pearl L H. 2000b “The ATPase cycle of HSP90 drives a molecular ‘clamp’ via transient dimerization of the N-terminal domains”, EMBO J., Vol. 19, pp. 4383-4392.
- Rajder et al, 2000, Ann. Neurol., Vol. 47, pp. 782.
- Roe S M, Prodromou C, O'Brien R, Ladbury J E, Piper P W and Pearl L H. 1999 “Structural basis for inhibition of the HSP90 molecular chaperone by the antitumour antibiotics radicicol and geldanamycin”, J. Med. Chem., Vol. 42, pp. 260-266.
- Rutherford S L and Lindquist S. 1998 “HSP90 as a capacitor for morphological evolution. Nature, Vol. 396, pp. 336-342.
- Schulte T W, Akinaga S, Murakata T, Agatsuma T, Sugimoto S, Nakano H, Lee Y S, Simen B B, Argon Y, Felts S, Toft D O, Neckers L M and Sharma S V. 1999 “Interaction of radicicol with members of the heat shock protein 90 family of molecular chaperones”, Mol. Endocrinology, Vol. 13, pp. 1435-1448.
- Schulte T W, Akinaga S, Soga S, Sullivan W, Sensgard B, Toft D and Neckers L M. 1998 “Antibiotic radicicol binds to the N-terminal domain of HSP90 and shares important biologic activities with geldanamcyin”, Cell Stress and Chaperones, Vol. 3, pp. 100-108.
- Schulte T W and Neckers L M. 1998 “The benzoquinone ansamycin 17-allylamino-17-deemthoxygeldanamcyin binds to HSP90 and shares important biologic activities with geldanamycin”, Cancer Chemother. Pharmacol., Vol. 42, pp. 273-279.
- Sittler et al, 2001, Hum. Mol. Genet., Vol. 10, pp. 1307.
- Smith D F. 2001 “Chaperones in signal transduction”, in: Molecular chaperones in the cell (P Lund, ed.; Oxford University Press, Oxford and NY), pp. 165-178.
- Smith D F, Whitesell L and Katsanis E. 1998 “Molecular chaperones: Biology and prospects for pharmacological intervention”, Pharmacological Reviews, Vol. 50, pp. 493-513.
- Song H Y, Dunbar J D, Zhang Y X, Guo D and Donner D B. 1995 “Identification of a protein with homology to hsp90 that binds the type 1 tumour necrosis factor receptor”, J. Biol. Chem., Vol. 270, pp. 3574-3581.
- Stebbins C E, Russo A, Schneider C, Rosen N, Hartl F U and Pavletich N P. 1997 “Crystal structure of an HSP90-geldanamcyin complex: targeting of a protein chaperone by an antitumor agent”, Cell, Vol. 89, pp. 239-250.
- Supko J G, Hickman R L, Greyer M R and Malspeis L. 1995 “Preclinical pharmacologic evaluation of geldanamycin as an antitumour agent”, Cancer Chemother. Pharmacol., Vol. 36, pp. 305-315.
- Tratzelt et al, 1995, Proc. Nat. Acad. Sci., Vol. 92, pp. 2944.
- Trost et al, 1998, J. Clin. Invest., Vol. 101, pp. 855.
- Tytell M and Hooper P L. 2001 “Heat shock proteins: new keys to the development of cytoprotective therapies”, Emerging Therapeutic Targets, Vol. 5, pp. 267-287.
- Uehara U, Hod M, Takeuchi T and Umezawa H.1986 “Phenotypic change from transformed to normal induced by benzoquinoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus”, Mol. Cell. Biol., Vol. 6, pp. 2198-2206.
- Waxman, Lloyd H. Inhibiting hepatitis C virus processing and replication. (Merck & Co., Inc., USA). PCT Int. Appl. (2002), WO 0207761
- Winklhofer et al, 2001, J. Biol. Chem., Vol. 276, 45160.
- Whitesell L, Mimnaugh E G, De Costa B, Myers C E and Neckers L M. 1994 “Inhibition of heat shock protein HSP90-pp 60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation”, Proc. Natl. Acad. Sci. USA., Vol. 91, pp. 8324-8328.
- Yorgin et al. 2000 “Effects of geldanamycin, a heat-shock protein 90-binding agent, on T cell function and T cell nonreceptor protein tyrosine kinases”, J. Immunol., Vol 164(6), pp. 2915-2923.
- Young J C, Moarefi I and Hartl F U. 2001 “HSP90: a specialized but essential protein-folding tool”, J. Cell. Biol., Vol. 154, pp. 267-273.
- Zhao J F, Nakano H and Sharma S. 1995 “Suppression of RAS and MOS transformation by radicicol”, Oncogene, Vol. 11, pp. 161-173.
Claims (21)
1-11. (canceled)
12. A method of inhibiting HSP90 activity in mammals which method comprises administering to the mammal an amount of a compound of formula (I), or a salt or N-oxide thereof, effective to inhibit said HSP90 activity:
wherein
R2 is a group of formula (IA):
—(Ar1)m-(Alk1)p-(Z)r-(Alk2)s-Q (IA)
—(Ar1)m-(Alk1)p-(Z)r-(Alk2)s-Q (IA)
wherein in any compatible combination
Ar1 is an optionally substituted aryl or heteroaryl radical,
Alk1 and Alk2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals,
m, p, r and s are independently 0 or 1,
Z is —O—, —S—, —(C═O)—, —(C═S)—SO2—, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA—
wherein RA is hydrogen or C1-C6 alkyl, and
Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical;
R3 is hydrogen, an optional substituent, or an optionally substituted (C1C6)alkyl, aryl or heteroaryl radical; and
R4 is a carboxamide or sulfonamide group,
wherein the optional substituent is selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, hydroxy C1-C6 alkyl, mercapto, mercapto C1-C6 alkyl, C1-C6 alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, COORC, —CORC, —SO2RC, —CONH2, —SO2NH2, —CONHRC, —SO2NHRC, —CONRCRD, —SO2NRCRD, —NH2, —NHRC, —NRCRD, —OCONH2, —OCONHRC, —OCONRCRD, —NHCORC, —NHCOORC, —NHRDCOORC, —NHSO2ORC, —NRDSO2ORC, —NHCONH2, —NRCCONH2, —NHCONHRD, —NRCCONHRD, —NHCONHRCRD, and —NRCCONRCRD, wherein RC and RD are independently C1-C6 alkyl groups.
13-14. (canceled)
15. A pharmaceutical or veterinary composition comprising a compound of formula (I), or a salt or N-oxide thereof:
wherein
R2 is a group of formula (IA):
—(Ar1)m-(Alk1)p-(Z)r-(Alk2)s-Q (IA)
—(Ar1)m-(Alk1)p-(Z)r-(Alk2)s-Q (IA)
wherein in any compatible combination
Ar1 is an optionally substituted aryl or heteroaryl radical,
Alk1 and Alk2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals,
m, p, r and s are independently 0 or 1,
Z is —O—, —S—, —(C═O)—, —(C═S)—SO2—, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA—
wherein RA is hydrogen or C1-C6 alkyl, and
Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical;
R3 is hydrogen, an optional substituent, or an optionally substituted (C1C6)alkyl, aryl or heteroaryl radical; and
R4 is a carboxamide or sulfonamide group,
wherein the optional substituent is selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, hydroxy C1-C6 alkyl, mercapto, mercapto C1-C6 alkyl, C1-C6 alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, COORC, —CORC, —SO2RC, —CONH2—SO2NH2, —CONHRC, —SO2NHRC, —CONRCRD, —SO2NRCRD, —NH2, —NHRC, —NRCRD, —OCONH2, —OCONHRC, —OCONRCRD, —NHCORC, —NHCOORC, —NHRDCOORC, —NHSO2ORC, —NRDSO2ORC, —NHCONH2, —NRCCONH2, —NHCONHRD, —NRCCONHRD, —NHCONHRCRD, and —NRCCONRCRD, wherein RC and RD are independently C1-C6 alkyl groups,
in an amount effective to inhibit said HSP90 activity together with a pharmaceutically or veterinarily acceptable carrier.
16.-20. (canceled)
21. The method of claim 12 wherein m is 1, each of p, r and s is 0, and Q is hydrogen.
22. The method of claim 21 wherein R2 is optionally substituted phenyl, 2- or 3-thienyl, 2- or 3-furanyl, or 2-, 3- or 4-pyridinyl,
wherein the optional substituent is selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, hydroxy C1-C6 alkyl, mercapto, mercapto C1-C6 alkyl, C1-C6 alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, COORC, —CORC, —SO2RC, —CONH2, —SO2NH2, —CONHRC, —SO2NHRC, —CONRCRD, —SO2NRCRD, —NH2, —NHRC, —NRCRD, —OCONH2, —OCONHRC, —OCONRCRD, —NHCORC, —NHCOORC, —NHRDCOORC, —NHSO2ORC, —NRDSO2ORC, —NHCONH2, —NRCCONH2, —NHCONHRD, —NRC CONHRD, —NHCONHRCRD, and —NRCCONRCRD, wherein RC and RD are independently C1-C6 alkyl groups.
23. The method of claim 21 wherein R2 is phenyl, optionally substituted by methyl, ethyl, n- or isopropyl, methoxy, ethoxy, isopropoxy, chloro, or bromo,
wherein the optional substituent is selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, hydroxy C1-C6 alkyl, mercapto, mercapto C1-C6 alkyl, C1-C6 alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, COORC, —CORC, —SO2RC, —CONH2, —SO2NH2, —CONHRC, —SO2NHRC, —CONRCRD, —SO2NRCRD, —NH2, —NHRC, —NRCRD, —OCONH2, —OCONHRC, —OCONRCRD, —NHCORC, —NHCOORC, —NHRDCOORC, —NHSO2ORC, —NRDSO2ORC, —NHCONH2, —NRCCONH2, —NHCONHRD, —NRC CONHRD, —NHCONHRCRD, and —NRCCONRCRD, wherein RC and RD are independently C1-C6 alkyl groups.
24. The method of claim 22 wherein the optional substituent is in the 4-position of the phenyl ring.
25. The method of claim 12 wherein m is 1, and p, r and s are 0, and Q is an optionally substituted carbocyclic or heterocyclic ring,
wherein the optional substituent is selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, hydroxy C1-C6 alkyl, mercapto, mercapto C1-C6 alkyl, C1-C6 alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, COORC, —CORC, —SO2RC, —CONH2, —SO2NH2, —CONHRC, —SO2NHRC, —CONRCRD, —SO2NRCRD, —NH2, —NHRC, —NRCRD, —OCONH2, —OCONHRC, —OCONRCRD, —NHCORC, —NHCOORC, —NHRDCOORC, —NHSO2ORC, —NRDSO2ORC, —NHCONH2, —NRCCONH2, —NHCONHRD, —NRC CONHRD, —NHCONHRCRD, and —NRCCONRCRD, wherein RC and RD are independently C1-C6 alkyl groups.
26. The method of claim 12 wherein Ar1 is a phenyl or pyridyl ring.
27. The method of claim 12 wherein R3 is amino(NH2).
28. The method of claim 12 wherein R4 is a carboxamide group of formula —CONRB(Alk)nRA wherein
Alk is a divalent alkylene, alkenylene or alkynylene radical, and the Alk radical may be optionally substituted,
n is 0 or 1,
RB is hydrogen or a C1-C6 alkyl or C2-C6 alkenyl group,
RA is hydroxy or optionally substituted carbocyclic or heterocyclyl, any of which heterocyclic rings may be substituted; or
RA and RB taken together with the nitrogen to which they are attached form an N-heterocyclic ring which may optionally contain one or more additional hetero atoms selected from O, S and N, and which may optionally be substituted on one or more ring C or N atoms;
wherein the optional substituent is selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, hydroxy C1-C6 alkyl, mercapto, mercapto C1-C6 alkyl, C1-C6 alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, COORC, —CORC, —SO2RC, —CONH2, —SO2NH2, —CONHRC, —SO2NHRC, —CONRCRD, —SO2NRCRD, —NH2, —NHRC, —NRCRD, —OCONH2, —OCONHRC, —OCONRCRD, —NHCORC, —NHCOORC, —NHRDCOORC, —NHSO2ORC, —NRDSO2ORC, —NHCONH2, —NRCCONH2, —NHCONHRD, —NRCCONHRD, —NHCONHRCRD, and —NRCCONRCRD, wherein RC and RD are independently C1-C6 alkyl groups.
29. The composition of claim 15 wherein m is 1, each of p, r and s is 0, and Q is hydrogen.
30. The composition of claim 29 wherein R2 is optionally substituted phenyl, 2- or 3-thienyl, 2- or 3-furanyl, or 2-, 3- or 4-pyridinyl,
wherein the optional substituent is selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, hydroxy C1-C6 alkyl, mercapto, mercapto C1-C6 alkyl, C1-C6 alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, COORC, —CORC, —SO2RC, —CONH2, —SO2NH2, —CONHRC, —SO2NHRC, —CONRCRD, —SO2NRCRD, —NH2, —NHRC, —NRCRD, —OCONH2, —OCONHRC, —OCONRCRD, —NHCORC, —NHCOORC, —NHRDCOORC, —NHSO2ORC, —NRDSO2ORC, —NHCONH2, —NRCCONH2, —NHCONHRD, —NRC CONHRD, —NHCONHRCRD, and —NRCCONRCRD, wherein RC and RD are independently C1-C6 alkyl groups.
31. The composition of claim 29 wherein R2 is phenyl, optionally substituted by methyl, ethyl, n- or isopropyl, methoxy, ethoxy, isopropoxy, chloro, or bromo,
wherein the optional substituent is selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, hydroxy C1-C6 alkyl, mercapto, mercapto C1-C6 alkyl, C1-C6 alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, COORC, —CORC, —SO2RC, —CONH2, —SO2NH2, —CONHRC, —SO2NHRC, —CONRCRD, —SO2NRCRD, —NH2, —NHRC, —NRCRD, —OCONH2, —OCONHRC, —OCONRCRD, —NHCORC, —NHCOORC, —NHRDCOORC, —NHSO2ORC, —NRDSO2ORC, —NHCONH2, —NRCCONH2, —NHCONHRD, —NRC CONHRD, —NHCONHRCRD, and —NRCCONRCRD, wherein RC and RD are independently C1-C6 alkyl groups.
32. The composition of claim 30 wherein the optional substituent is in the 4-position of the phenyl ring.
33. The composition of claim 15 wherein m is 1, and p, r and s are 0, and Q is an optionally substituted carbocyclic or heterocyclic ring,
wherein the optional substituent is selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, hydroxy C1-C6 alkyl, mercapto, mercapto C1-C6 alkyl, C1-C6 alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, COORC, —CORC, —SO2RC, —CONH2, —SO2NH2, —CONHRC, —SO2NHRC, —CONRCRD, —SO2NRCRD, —NH2, —NHRC, —NRCRD, —OCONH2, —OCONHRC, —OCONRCRD, —NHCORC, —NHCOORC, —NHRDCOORC, —NHSO2ORC, —NRDSO2ORC, —NHCONH2, —NRCCONH2, —NHCONHRD, —NRC CONHRD, —NHCONHRCRD, and —NRCCONRCRD, wherein RC and RD are independently C1-C6 alkyl groups.
34. The composition of claim 15 wherein Ar1 is a phenyl or pyridyl ring.
35. The composition of claim 15 wherein R3 is amino(NH2).
36. The composition of claim 15 wherein R4 is a carboxamide group of formula —CONRB(Alk)nRA wherein
Alk is a divalent alkylene, alkenylene or alkynylene radical, and the Alk radical may be optionally substituted,
n is 0 or 1,
RB is hydrogen or a C1-C6 alkyl or C2-C6 alkenyl group,
RA is hydroxy or optionally substituted carbocyclic or heterocyclyl, any of which heterocyclic rings may be substituted; or
RA and RB taken together with the nitrogen to which they are attached form an N-heterocyclic ring which may optionally contain one or more additional hetero atoms selected from O, S and N, and which may optionally be substituted on one or more ring C or N atoms;
wherein the optional substituent is selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, hydroxy C1-C6 alkyl, mercapto, mercapto C1-C6 alkyl, C1-C6 alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, COORC, —CORC, —SO2RC, —CONH2, —SO2NH2, —CONHRC, —SO2NHRC, —CONRCRD, —SO2NRCRD, —NH2, —NHRC, —NRCRD, —OCONH2, —OCONHRC, —OCONRCRD, —NHCORC, —NHCOORC, —NHRDCOORC, —NHSO2ORC, —NRDSO2ORC, —NHCONH2, —NRCCONH2, —NHCONHRD, —NRCCONHRD, —NHCONHRCRD, and —NRCCONRCRD, wherein RC and RD are independently C1-C6 alkyl groups.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/909,014 US20110034457A1 (en) | 2003-10-10 | 2010-10-21 | Pyridothiophene Compounds |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0323810.2A GB0323810D0 (en) | 2003-10-10 | 2003-10-10 | Pyridothiophene compounds |
GB0323810.2 | 2003-10-10 | ||
PCT/GB2004/004216 WO2005034950A1 (en) | 2003-10-10 | 2004-10-05 | Pyridothiophene compounds |
US57478807A | 2007-01-19 | 2007-01-19 | |
US12/909,014 US20110034457A1 (en) | 2003-10-10 | 2010-10-21 | Pyridothiophene Compounds |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2004/004216 Continuation WO2005034950A1 (en) | 2003-10-10 | 2004-10-05 | Pyridothiophene compounds |
US57478807A Continuation | 2003-10-10 | 2007-01-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
US20110034457A1 true US20110034457A1 (en) | 2011-02-10 |
Family
ID=29433707
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/574,788 Abandoned US20070213328A1 (en) | 2003-10-10 | 2004-10-05 | Pyridothiophene Compounds |
US12/909,014 Abandoned US20110034457A1 (en) | 2003-10-10 | 2010-10-21 | Pyridothiophene Compounds |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/574,788 Abandoned US20070213328A1 (en) | 2003-10-10 | 2004-10-05 | Pyridothiophene Compounds |
Country Status (4)
Country | Link |
---|---|
US (2) | US20070213328A1 (en) |
EP (1) | EP1680108A1 (en) |
GB (1) | GB0323810D0 (en) |
WO (1) | WO2005034950A1 (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102005009440A1 (en) * | 2005-03-02 | 2006-09-07 | Merck Patent Gmbh | thienopyridine derivatives |
FR2885904B1 (en) | 2005-05-19 | 2007-07-06 | Aventis Pharma Sa | NOVEL FLUORENE DERIVATIVES, COMPOSITIONS CONTAINING SAME AND USE THEREOF |
DE102005024245A1 (en) * | 2005-05-27 | 2006-11-30 | Merck Patent Gmbh | thienopyridines |
FR2907453B1 (en) | 2006-10-24 | 2008-12-26 | Sanofi Aventis Sa | NOVEL FLUORENE DERIVATIVES, COMPOSITIONS CONTAINING SAME AND USE THEREOF |
DE102007049451A1 (en) * | 2007-10-16 | 2009-04-23 | Merck Patent Gmbh | 5-Cyano-thienopyridine |
MX2011008988A (en) | 2009-02-27 | 2011-12-16 | Siga Technologies Inc | Thienopyridine derivatives for the treatment and prevention of dengue virus infections. |
EP2655345B1 (en) | 2010-12-20 | 2015-02-18 | SIGMA-TAU Research Switzerland S.A. | Aryl triazole compounds with antitumoural activity |
AU2012282905B8 (en) | 2011-07-08 | 2017-08-31 | Cornell University | Uses of labeled HSP90 inhibitors |
PL3904350T3 (en) * | 2018-04-12 | 2024-02-19 | Bayer Aktiengesellschaft | N-(cyclopropylmethyl)-5-(methylsulfonyl)-n-{1-[1-(pyrimidin-2-yl)-1h-1,2,4-triazol-5-yl]ethyl}benzamide derivatives and the corresponding pyridine-carboxamide derivatives as pesticides |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DD275688A1 (en) * | 1988-09-27 | 1990-01-31 | Univ Leipzig | PROCESS FOR THE PREPARATION OF 6-AMINOTHIENO / 2,3-B / PYRIDINES |
AU3262593A (en) * | 1992-01-11 | 1993-08-03 | Schering Agrochemicals Limited | Biheterocyclic fungicidal compounds |
AU2002343604C1 (en) * | 2001-10-30 | 2009-09-17 | Conforma Therapeutics Corporation | Purine analogs having HSP90-inhibiting activity |
CA2508780A1 (en) * | 2002-12-12 | 2004-07-01 | Pharmacia Corporation | Method of using aminocyanopyridine compounds as mitogen activated protein kinase-activated protein kinase-2 inhibitors |
-
2003
- 2003-10-10 GB GBGB0323810.2A patent/GB0323810D0/en not_active Ceased
-
2004
- 2004-10-05 EP EP04768755A patent/EP1680108A1/en not_active Withdrawn
- 2004-10-05 WO PCT/GB2004/004216 patent/WO2005034950A1/en active Application Filing
- 2004-10-05 US US10/574,788 patent/US20070213328A1/en not_active Abandoned
-
2010
- 2010-10-21 US US12/909,014 patent/US20110034457A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
US20070213328A1 (en) | 2007-09-13 |
WO2005034950A1 (en) | 2005-04-21 |
EP1680108A1 (en) | 2006-07-19 |
GB0323810D0 (en) | 2003-11-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7728016B2 (en) | Substituted 5-membered ring compounds and their use | |
US8642594B2 (en) | Substituted thieno[2,3-d]pyrimidines as HSP90 inhibitors | |
US7803831B2 (en) | 3-(2-hydroxy-phenyl)-1H-pyrazole-4-carboxylic acid amide derivatives as HSP90 inhibitors for the treatment of cancer | |
US20110034457A1 (en) | Pyridothiophene Compounds | |
JP4891904B2 (en) | Pyrimidothiophene compound | |
US7612201B2 (en) | Pyrazole compounds | |
EP2007767B1 (en) | Pyrrolopyrimidine derivatives used as hsp90 inhibitors | |
US20090181989A1 (en) | Purine Compunds as HSP90 Protein Inhibitors for the Treatment of Cancer | |
US20100010037A1 (en) | 1h-pyrrolo[2,3-b]pyridine derivatives useful as hsp90 inhibitors | |
US20090054421A1 (en) | Pyrimidothiophene Compounds Having HSP90 Inhibitory Activity | |
MXPA06002118A (en) | Pyrimidothiophene compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |